Calcium is well known to play various and important roles in living organisms and cells. In the past, the present inventors discovered that 2-APB (2-aminoethyl diphenyl borinate) acts to modulate the intracellular calcium concentration (Non-Patent Literature 1), and then synthesized about 500 different boron compounds analogous to 2-APB and examined calcium concentration modulating activities of these compounds (Patent Literatures 1 to 4). As a result, it was revealed that these compounds function to modulate an intracellular calcium concentration associated with SOCE (store operated calcium entry) or IICR (IP3 induced calcium release). In addition, it was found that some of the compounds have transglutaminase-inhibiting activities, in addition to the above-mentioned activities.
It has been revealed that abnormal crosslinking reactions of certain proteins cause intractable diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease, Celiac disease, cataract, mad cow disease, congenital lamellar ichthyosis, and congenital hemostatic disorder (Non-Patent Literatures 2 to 4). In particular, an enzyme that is thought to be involved in abnormal protein crosslinking reactions is transglutaminase.
Transglutaminase is an enzyme that is activated in the presence of calcium. Recently, it has been known that transglutaminase is involved in the development of neurological diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. Thus, transglutaminase inhibitors are thought to be effective drugs for treatment of such diseases (Non-Patent Literatures 5 and 6).
The main reaction of the abnormal protein crosslinking is a reaction in which isopeptide bonds are formed from the amide group of glutamine and the amino group of lysine of a protein through deammoniation. The mechanism revealing that inhibitors of the enzyme capable of inducing such reaction (i.e., transglutaminase) would be effective for treatment of the aforementioned diseases or the like has been clarified (Non-Patent Literature 7). Based on these findings, there are increasing researches to develop transglutaminase inhibitors as therapeutic drugs for diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease, Celiac disease, cataract, mad cow disease, congenital lamellar ichthyosis, congenital hemostatic disorder, liver disorder, autoimmune disease, and cerebral infarction (Non-Patent Literatures 8 to 13).